The Influence and Regulation of Neuronal ROCK Signaling by IGF-1

IGF-1 对神经元 ROCK 信号传导的影响和调节

• 批准号: 8832449
• 负责人: Nicole M Ashpole
• 金额: $ 5.33万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8832449
• 关键词: Address; Age; Age-associated memory impairment; Aging; Animal Model; Animals; Area; Behavioral; Biological Assay; Brain; Caregivers; Cells; Cognition; Cognitive deficits; Data; Development; Elderly; Ensure; Environment; Etiology; Foundations; Funding; Goals; Growth; Growth Factor; Hippocampus (Brain); Human; Impaired cognition; Impairment; In Vitro; Insulin-Like Growth Factor I; Investigation; Knowledge; Laboratories; Lead; Learning; Long-Term Potentiation; Maintenance; Measures; Memory; Mentors; Molecular; Mus; Neurites; Neuronal Differentiation; Neuronal Plasticity; Neurons; Neurosciences; Neurosecretory Systems; Pathway interactions; Patients; Peer Review; Phosphotransferases; Play; Positioning Attribute; Postdoctoral Fellow; Protein Kinase; Publications; Quality of life; Rattus; Regulation; Research; Research Personnel; Role; Scientist; Signal Pathway; Signal Transduction; Somatotropin; Structure; Supplementation; Synapses; Synaptic plasticity; Techniques; Training; Training Programs; Up-Regulation; Vertebral column; age related; aged; aging population; authority; base; career; experience; improved; in vivo; interest; member; mouse model; neurofilament; neuronal growth; novel; programs; public health relevance; research study; rho; therapeutic target

 DESCRIPTION (provided by applicant): The long-term career goal of Dr. Ashpole is to establish herself as a successful and well-funded, independent investigator in the field of aging, and in particular, the area of neuroscience. Thus far in her training career, Dr. Ashpole has been highly-productive with 12 peer-reviewed publications. Her doctoral training, in which she studied intracellular signaling cascades in neurons, laid a strong foundation for her current post-doctoral position. For this, Dr. Ashpole joined the laboratory of Dr. William Sonntag to study the mechanisms underlying IGF-1-dependent changes in learning and memory. Dr. Sonntag is a leading authority in the field of neuroendocrine signaling and aging. Dr. Sonntag's laboratory offers a variety of in vivo approaches which will expand her technique repertoire and allow her to become a well-rounded research scientist. The research strategy outlined in this proposal incorporates the in vitro techniques used to study signaling cascades from her doctoral training with the in vivo techniques in the Sonntag laboratory. The training program includes a mixture of laboratory training and mentoring interactions with Dr. Sonntag and an advisory council. Together, this program will ensure the Dr. Ashpole transitions to an independent investigator in the field of aging. The age-dependent loss of IGF-1 has been shown to contribute to cognitive impairment; however, the pathophysiological mechanisms underlying this effect remain to be established. The proposed studies will address this gap in knowledge by examining potential signaling pathways that may induce changes in neuronal structure and function when IGF-1 is reduced. Our preliminary data indicates that IGF-1 inhibition leads to the upregulation of the Rho-associated protein kinase (ROCK). Dr. Ashpole hypothesizes that this IGF-1- dependent upregulation of ROCK contributes to age-related impairments in learning and memory, as RhoA/ROCK activity is known to negatively influence neuronal structure and function. To better understand how IGF-1-regulated ROCK contributes to age-related cognitive decline, Dr. Ashpole will first examine the mechanisms by which IGF-1 regulates ROCK activity in Specific Aim 1. In Specific Aim 2, Dr. Ashpole will examine the effects of IGF-1-regulated ROCK on neuronal structure. Finally, in Specific Aim 3, Dr. Ashpole will examine how IGF-1-regulated ROCK influences neuronal function by measuring long-term potentiation as well as learning and memory within our mouse models. While growth hormones are often recognized solely for their contribution to cell development, it is obvious that IGF-1 plays an important role in maintaining neuronal function throughout our lifetime. Thus, this proposal addresses an area of research that is of high relevance in the field of aging. The studies that have been proposed will explore novel pathways that contribute to cognitive impairment when IGF-1 is reduced in advanced aging. Because of this, findings from this project may have long-term implications in improving the quality of life in the aging population.

 描述（由应用程序提供）：Ashpole博士的长期职业目标是将自己确立为衰老领域，尤其是神经科学领域的成功，资金充足的独立调查员。在她的培训生涯中，Ashpole博士在12个经过同行评审的出版物中一直非常有生产力。她在神经元中学习细胞内信号级联的博士培训为她目前的博士后奠定了坚实的基础 位置。为此，Ashpole博士加入了William Sonntag博士的实验室，研究了学习和记忆中IGF-1依赖性变化的机制。 Sonntag博士是神经内分泌信号和衰老领域的领先权威。 Sonntag博士的实验室提供了各种体内方法，这些方法将扩大她的技术曲目，并使她成为一名全面的研究科学家。该提案中概述的研究策略结合了用于研究Sonntag实验室中体内技术的博士培训的信号级联技术的体外技术。该培训计划包括与Sonntag博士和咨询委员会的实验室培训和心理互动的混合。该计划将共同确保Ashpole博士过渡到老化领域的独立研究者。 IGF-1的年龄依赖性损失已显示出有助于认知障碍。但是，这种作用的基础病理生理机制仍有待确定。拟议的研究将通过检查潜在的信号传导途径来解决这一差距，从而在IGF-1降低时可能诱导神经元结构和功能变化的潜在信号通路。我们的初步数据表明，IGF-1抑制作用导致Rho相关蛋白激酶（ROCK）的上调。 Ashpole博士假设岩石的这种IGF-1依赖性更新有助于与年龄相关的学习和记忆中的障碍，因为Rhoa/Rock活动已知会对神经元的结构和功能产生负面影响。为了更好地了解IGF-1调节的岩石如何有助于与年龄相关的认知下降，Ashpole博士将首先研究IGF-1在特定目标1中调节岩石活动的机制。在特定目标2中，Ashpole博士将研究IGF-1调节岩石对神经元结构的影响。最后，在特定的目标3中，Ashpole博士将通过测量长期增强以及我们的小鼠模型中的学习和记忆来检查IGF-1调节的岩石如何影响神经元功能。虽然通常仅因其对细胞发育的贡献而被认可，但很明显，IGF-1在我们一生中保持神经元功能方面起着重要作用。这是该建议介绍在衰老领域具有很高相关性的研究领域。提出的研究将探索当高级衰老减少IGF-1时导致认知障碍的新途径。因此，该项目的发现可能对改善人口老龄化的生活质量具有长期影响。